12-56042173-A-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001029.5(RPS26):​c.3+4A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,613,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

RPS26
NM_001029.5 splice_region, intron

Scores

2
Splicing: ADA: 0.1264
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.53
Variant links:
Genes affected
RPS26 (HGNC:10414): (ribosomal protein S26) This gene encodes a ribosomal protein that is a component of the 40S subunit. The protein belongs to the S26E family of ribosomal proteins. Mutations in this gene are found in Diamond-Blackfan anemia 10. There are multiple processed pseudogenes of this gene dispersed through the genome. [provided by RefSeq, Aug 2017]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.48).
BS2
High AC in GnomAdExome4 at 30 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RPS26NM_001029.5 linkc.3+4A>C splice_region_variant, intron_variant Intron 1 of 3 ENST00000646449.2 NP_001020.2 P62854A0A024RB14

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RPS26ENST00000646449.2 linkc.3+4A>C splice_region_variant, intron_variant Intron 1 of 3 NM_001029.5 ENSP00000496643.1 P62854
RPS26ENST00000356464.10 linkc.3+4A>C splice_region_variant, intron_variant Intron 2 of 4 1 ENSP00000348849.5 P62854
RPS26ENST00000552361.1 linkc.3+4A>C splice_region_variant, intron_variant Intron 2 of 4 5 ENSP00000450339.1 P62854
RPS26ENST00000548590.1 linkn.30+4A>C splice_region_variant, intron_variant Intron 1 of 2 5

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
151968
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000358
AC:
9
AN:
251362
Hom.:
0
AF XY:
0.0000662
AC XY:
9
AN XY:
135862
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000185
Gnomad NFE exome
AF:
0.0000440
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000205
AC:
30
AN:
1461840
Hom.:
0
Cov.:
35
AF XY:
0.0000289
AC XY:
21
AN XY:
727222
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000131
Gnomad4 NFE exome
AF:
0.0000180
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
151968
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74226
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
EpiCase
AF:
0.000109
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Diamond-Blackfan anemia 10 Uncertain:1
Sep 19, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 2042654). This variant has not been reported in the literature in individuals affected with RPS26-related conditions. This variant is present in population databases (rs201248213, gnomAD 0.02%). This sequence change falls in intron 1 of the RPS26 gene. It does not directly change the encoded amino acid sequence of the RPS26 protein. It affects a nucleotide within the consensus splice site. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.48
CADD
Benign
14
DANN
Benign
0.64
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.3

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.13
dbscSNV1_RF
Benign
0.41
SpliceAI score (max)
0.49
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.49
Position offset: 13

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs201248213; hg19: chr12-56435957; API